PHASE-I STUDY OF SIMULTANEOUS DOSE-ESCALATION AND SCHEDULE ACCELERATION OF CYCLOPHOSPHAMIDE-DOXORUBICIN-ETOPOSIDE USING GRANULOCYTE-COLONY-STIMULATING FACTOR WITH OR WITHOUT ANTIMICROBIAL PROPHYLAXIS IN PATIENTS WITH SMALL-CELL LUNG-CANCER

A phase I study was designed to assess whether dose intensity of an 'a ccelerated' cyclophosphamide-doxorubicin-etoposide (CDE) regimen plus granulocyte colony-stimulating factor (G-CSF) could be increased furth er, in an outpatient setting, by escalating the dose of each single dr ug of the regimen. Patients with previously untreated small-cell lung cancer (SCLC) received escalating doses of cyclophosphamide (C) 1100-1 300 mg m(-2) intravenously (i.v.) on day 1, doxorubicin (D) 50-60 mg m (-2) i.v. on day 1, etoposide (E) 110-130 mg m(-2) i.v. on days 1, 2, 3 and every 14 days for at least three courses. Along with chemotherap y, G-CSF (filgastrim) 5 mu g kg(-1) from day 5 to day 11 was administe red subcutaneously (s.c.) to all patients. Twenty-five patients were e nrolled into the study. All patients at the first dose level (C 1100, D 50, E 110 x 3) completed three or more cycles at the dose and schedu le planned by the protocol and no 'dose-limiting toxicity' (DLT) was s een. At the second dose level (C 1200, D 55, E 120 x 3) three out of f ive patients had a DLT consisting of 'granulocytopenic fever' (GCPF). Another six patients were treated at this dose level with the addition of ciprofloxacin 500 mg twice a day and only two patients had a DLT [ one episode of documented oral candidiasis and one of 'fever of unknow n origin' (FUO) with generalised mucositis]. Accrual of patients proce eded to the third dose level (C 1300, D 60, E 130 x 3) with the prophy lactic use of ciprofloxacin. Four out of six patients experienced a DL T consisting of GCPF or documented non-bacterial infection. Accrual of patients at the third dose level was then resumed adding to ciproflox acin anti-fungal prophylaxis (fluconazole 100 mg daily) and anti-viral prophylaxis (acyclovir 800 mg twice a day) from day 5 to 11. Out of f ive patients treated three experienced a DLT consisting of severe leuc openia and fever or infection. With a simultaneous dose escalation and schedule acceleration it is indeed possible to take maximum advantage of G-CSF activity and to increase CDE dose intensity by a factor 1.65 -1.80 for a maximum of 3-4 courses. The role of antimicrobial prophyla xis in this setting deserves to be investigated further.